Aiman Mohtar - Academia.edu (original) (raw)

Papers by Aiman Mohtar

BMC Cancer, Jul 23, 2021

Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a preval... more Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10,000 people globally. The cell surface proteins or surfaceome serve as information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation in surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in a cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have 'direct' access to drugs, they are appealing targets for cancer therapy. However, a comprehensive GBM surfaceome landscape has not been fully defined yet. Thus, this study aimed to define GBM-associated surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods: We integrated the RNA-Seq data from TCGA GBM (n = 166) and GTEx normal brain cortex (n = 408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by an integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the highconfidence GBM surfaceome signature. Results: Of the 2381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes was validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions: In summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.

Travel Medicine and Infectious Disease, May 1, 2021

American Journal of Physiology-cell Physiology, 2020

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the... more The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 "interactome" and discuss the pathological and physiological role of such AGR2 interactions.

Biomolecules, Feb 7, 2020

Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumo... more Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.

Frontiers in Oncology, Nov 19, 2019

Chemotherapy is the standard go-to treatment for cancer besides surgery and radiation. It has rec... more Chemotherapy is the standard go-to treatment for cancer besides surgery and radiation. It has recently come to light that the interaction between chemotherapy and the immune system is important in maintaining tumor immunity as well as influencing the efficacy of the therapy. However, ample preclinical studies have shown that in addition to direct cytotoxic effects on cancer cells, a fraction of chemotherapeutic agents may promote immunogenic cell death, and alter the inflammatory milieu of the tumor microenvironment. Extracellular vesicles (EV) have been shown to interact with the tumor microenvironment by delivering alterative signals to the surrounding cells; as a result, this results in interference with each cell's capability to eradicate tumors or gives advantages to cancer cells so as to survive therapy. Chemotherapy-induced extracellular vesicles (chemo-EVs) have been theorized to be carrying different cargo loads than non-chemotherapy-induced EVs. Aside from chemoresistance, there is growing evidence to suggest that chemo-EVs could dictate tumor behavior, especially in terms of metastasis, immune response, and cancer stemness. This mini-review attempts to summarize and evaluate recent developments on the role of chemo-EVs in other aspects of tumor-related processes.

Proteomics, Dec 11, 2018

Understanding the relationship between genotypes and phenotypes is essential to disentangle biolo... more Understanding the relationship between genotypes and phenotypes is essential to disentangle biological mechanisms and to unravel the molecular basis of diseases. Genes and proteins are closely linked in biological systems. However, genomics and proteomics have developed separately into two distinct disciplines whereby crosstalk among scientists from the two domains has been limited and this constrains the integration of both fields into a single data modality of useful information. The emerging field of proteogenomics attempts to address this by building bridges between the two disciplines. In this review, we briefly discuss how genomics and transcriptomics data in different formats can be utilized to assist proteogenomics application. Subsequently, a much larger part of this review focuses on proteogenomics research that are published in the last five years that answer two important questions. Firstly, we discuss how proteogenomics can be applied to tackle biological problems, covering genome annotation and precision medicine. Secondly, we cover the latest developments in analytical technologies for data acquisition and the bioinformatics tools to interpret and visualize proteogenomics data.

Seminars in Cancer Biology, Aug 1, 2015

Proteins targeted to secretory pathway enter the endoplasmic reticulum where they undergo posttra... more Proteins targeted to secretory pathway enter the endoplasmic reticulum where they undergo posttranslational modification and subsequent quality control executed by exquisite catalysts of protein folding, protein disulphide isomerases (PDIs). These enzymes can often provide strict conformational protein folding solutions to highly cysteine-rich cargo as they facilitate disulphide rearrangement in the endoplasmic reticulum. Under conditions when PDI substrates are not isomerised properly, secreted proteins can accumulate in the endoplasmic reticulum leading to endoplasmic reticulum stress initiation with implications for human disease development. Anterior Gradient-2 (AGR2) is an endoplasmic reticulum-resident PDI superfamily member that has emerged as a dominant effector of basic biological properties in vertebrates including blastoderm formation and limb regeneration. AGR2 perturbation in mammals influences disease processes including cancer progression and drug resistance, asthma, and inflammatory bowel disease. This review will focus on the molecular characteristics, function, and regulation of AGR2, views on its emerging biological functions and misappropriation in disease, and prospects for therapeutic intervention into endoplasmic reticulum-resident protein folding pathways for improving the treatment of human disease.

International Journal of Molecular Sciences, Mar 29, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Biological Chemistry, Mar 1, 2013

Background: Cytochrome c maturation (Ccm) is the covalent ligation of heme b to an apocytochrome ... more Background: Cytochrome c maturation (Ccm) is the covalent ligation of heme b to an apocytochrome c. Results: CcmE forms a stable ternary complex with CcmI and apocytochrome c. Conclusion: Together with CcmFHI, the heme chaperone CcmE is a part of the heme ligation complex that matures apocytochromes c. Significance: These findings contribute to our mechanistic understanding of how the Ccm process occurs in cells. Cytochrome c maturation (Ccm) is a post-translational process that occurs after translocation of apocytochromes c to the positive (p) side of energy-transducing membranes. Ccm is responsible for the formation of covalent bonds between the thiol groups of two cysteines residues at the heme-binding sites of the apocytochromes and the vinyl groups of heme b (protoporphyrin IX-Fe). Among the proteins (CcmABCDEFGHI and CcdA) required for this process, CcmABCD are involved in loading heme b to apoCcmE. The holoCcmE thus formed provides heme b to the apocytochromes. Catalysis of the thioether bonds between the apocytochromes c and heme b is mediated by the heme ligation core complex, which in Rhodobacter capsulatus contains at least the CcmF, CcmH, and CcmI components. In this work we show that the heme chaperone apoCcmE binds to the apocytochrome c and the apocytochrome c chaperone CcmI to yield stable binary and ternary complexes in the absence of heme in vitro. We found that during these protein-protein interactions, apoCcmE favors the presence of a disulfide bond at the apocytochrome c heme-binding site. We also establish using detergent-dispersed membranes that apoCcmE interacts directly with CcmI and CcmH of the heme ligation core complex CcmFHI. Implications of these findings are discussed with respect to heme transfer from CcmE to the apocytochromes c during heme ligation assisted by the core complex CcmFHI.

Biomolecules, Mar 31, 2021

Research Square (Research Square), Jul 28, 2020

Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a preval... more Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10000 people globally. The cell surface proteins or surfaceome serve as an information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation of surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in cell-based system identi ed that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have 'direct' access to drugs, they are appealing targets for cancer therapy. However, a comprehensive aberrant GBM surfaceome landscape has not been fully de ned. Thus, this study aimed to de ne GBM-speci c surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods: We integrated the RNA-Seq data from TCGA GBM (n=166) and GTEx normal brain cortex (n=408) databases to identify the signi cantly dysregulated surfaceome in GBM. This was followed by integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-con dence GBM surfaceome signature. Results: Of the 2,381 signi cantly dysregulated genes in GBM, 395 genes were classi ed as surfaceome. Via the integrative analysis, we identi ed 6 high-con dence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were signi cantly upregulated in GBM. The expression of these genes were validated in an independent transcriptomics database, which con rmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is signi cantly associated with poor disease-free survival. Last, using the Drugbank database, we identi ed several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions: In summary, we identi ed and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to e cient diagnostic/prognostic markers or potential treatment options for GBM.

Frontiers in Pediatrics, Mar 11, 2021

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and ... more Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.

Biosensors, Jun 7, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Cancers

Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic a... more Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease’s metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facili...

International Journal of Molecular Sciences

Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-alle... more Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGF...

Frontiers in Pediatrics

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and ... more Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down ...

Cells

Breast cancer is the leading cause of cancer-related deaths in women. The aggressive breast cance... more Breast cancer is the leading cause of cancer-related deaths in women. The aggressive breast cancer subtype is commonly linked to the genetic alterations in the TP53 tumor suppressor gene, predominantly the missense mutations. Robust experimental models are needed to gain better insights into these mutations’ molecular properties and implications in tumorigenesis. The generation of such models harboring the alterations is feasible with the CRISPR-based gene editing technology. Moreover, the development of new CRISPR applications, particularly DNA base and prime editing, has considerably improved the precision and versatility of gene editing. Here, we employed the prime editing tool to revert a TP53 missense C > T mutation (L194F) in a T47D luminal A breast cancer cell line. In parallel, this prime editing tool was also utilized to introduce the L194F mutation in HEK293T cells. To assess the prime editing efficiency in both cell lines, we first performed Sanger sequencing in the pr...

Journal of Biomedical Science, 2022

A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encod... more A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encoded protein (SEP) which comprises ≤ 100 amino acids. Traditionally dismissed by genome annotation pipelines as meaningless noise, sORFs were found to possess coding potential with ribosome profiling (RIBO-Seq), which unveiled sORF-based transcripts at various genome locations. Nonetheless, the existence of corresponding microproteins that are stable and functional was little substantiated by experimental evidence initially. With recent advancements in multi-omics, the identification, validation, and functional characterisation of sORFs and microproteins have become feasible. In this review, we discuss the history and development of an emerging research field of sORFs and microproteins. In particular, we focus on an array of bioinformatics and OMICS approaches used for predicting, sequencing, validating, and characterizing these recently discovered entities. These strategies include RIBO-S...

Additional file 2 Supplementary Fig. S1. Gene ontology and deregulated pathways in GBM. (A-B) Gen... more Additional file 2 Supplementary Fig. S1. Gene ontology and deregulated pathways in GBM. (A-B) Gene ontology cellular component of the significantly (A) upregulated and (B) downregulated genes in GBM. (C-D) KEGG pathway analysis of the (C) upregulated and (D) downregulated genes in GBM. Supplementary Fig. S2. Significant differentially expressed cell-surface genes in GBM. (A) GBM surfaceome classification using previously annotated cell surface genes dataset identifies 395 DEGs that belongs to surfaceome. (B) Cell surface genes stratification from (A) based on its subclass. Supplementary Fig. S3. KEGG pathway analysis of differentially expressed surfaceome in GBM. (A) Upregulated surfaceome and (B) Downregulated surfaceome. Supplementary Fig. S4. Mapping the expression of 87-gene modules from (Fig. 4A) with scRNA-seq data from [26] on the basis of GBM cell microenvironment. Supplementary Fig. S5. Significant upregulation of the prioritized GBM surfaceome signature in GBM patients. (A...

BMC Cancer, Jul 23, 2021

Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a preval... more Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10,000 people globally. The cell surface proteins or surfaceome serve as information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation in surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in a cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have 'direct' access to drugs, they are appealing targets for cancer therapy. However, a comprehensive GBM surfaceome landscape has not been fully defined yet. Thus, this study aimed to define GBM-associated surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods: We integrated the RNA-Seq data from TCGA GBM (n = 166) and GTEx normal brain cortex (n = 408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by an integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the highconfidence GBM surfaceome signature. Results: Of the 2381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes was validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions: In summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.

Travel Medicine and Infectious Disease, May 1, 2021

American Journal of Physiology-cell Physiology, 2020

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the... more The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 "interactome" and discuss the pathological and physiological role of such AGR2 interactions.

Biomolecules, Feb 7, 2020

Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumo... more Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.

Frontiers in Oncology, Nov 19, 2019

Chemotherapy is the standard go-to treatment for cancer besides surgery and radiation. It has rec... more Chemotherapy is the standard go-to treatment for cancer besides surgery and radiation. It has recently come to light that the interaction between chemotherapy and the immune system is important in maintaining tumor immunity as well as influencing the efficacy of the therapy. However, ample preclinical studies have shown that in addition to direct cytotoxic effects on cancer cells, a fraction of chemotherapeutic agents may promote immunogenic cell death, and alter the inflammatory milieu of the tumor microenvironment. Extracellular vesicles (EV) have been shown to interact with the tumor microenvironment by delivering alterative signals to the surrounding cells; as a result, this results in interference with each cell's capability to eradicate tumors or gives advantages to cancer cells so as to survive therapy. Chemotherapy-induced extracellular vesicles (chemo-EVs) have been theorized to be carrying different cargo loads than non-chemotherapy-induced EVs. Aside from chemoresistance, there is growing evidence to suggest that chemo-EVs could dictate tumor behavior, especially in terms of metastasis, immune response, and cancer stemness. This mini-review attempts to summarize and evaluate recent developments on the role of chemo-EVs in other aspects of tumor-related processes.

Proteomics, Dec 11, 2018

Understanding the relationship between genotypes and phenotypes is essential to disentangle biolo... more Understanding the relationship between genotypes and phenotypes is essential to disentangle biological mechanisms and to unravel the molecular basis of diseases. Genes and proteins are closely linked in biological systems. However, genomics and proteomics have developed separately into two distinct disciplines whereby crosstalk among scientists from the two domains has been limited and this constrains the integration of both fields into a single data modality of useful information. The emerging field of proteogenomics attempts to address this by building bridges between the two disciplines. In this review, we briefly discuss how genomics and transcriptomics data in different formats can be utilized to assist proteogenomics application. Subsequently, a much larger part of this review focuses on proteogenomics research that are published in the last five years that answer two important questions. Firstly, we discuss how proteogenomics can be applied to tackle biological problems, covering genome annotation and precision medicine. Secondly, we cover the latest developments in analytical technologies for data acquisition and the bioinformatics tools to interpret and visualize proteogenomics data.

Seminars in Cancer Biology, Aug 1, 2015

Proteins targeted to secretory pathway enter the endoplasmic reticulum where they undergo posttra... more Proteins targeted to secretory pathway enter the endoplasmic reticulum where they undergo posttranslational modification and subsequent quality control executed by exquisite catalysts of protein folding, protein disulphide isomerases (PDIs). These enzymes can often provide strict conformational protein folding solutions to highly cysteine-rich cargo as they facilitate disulphide rearrangement in the endoplasmic reticulum. Under conditions when PDI substrates are not isomerised properly, secreted proteins can accumulate in the endoplasmic reticulum leading to endoplasmic reticulum stress initiation with implications for human disease development. Anterior Gradient-2 (AGR2) is an endoplasmic reticulum-resident PDI superfamily member that has emerged as a dominant effector of basic biological properties in vertebrates including blastoderm formation and limb regeneration. AGR2 perturbation in mammals influences disease processes including cancer progression and drug resistance, asthma, and inflammatory bowel disease. This review will focus on the molecular characteristics, function, and regulation of AGR2, views on its emerging biological functions and misappropriation in disease, and prospects for therapeutic intervention into endoplasmic reticulum-resident protein folding pathways for improving the treatment of human disease.

International Journal of Molecular Sciences, Mar 29, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Biological Chemistry, Mar 1, 2013

Background: Cytochrome c maturation (Ccm) is the covalent ligation of heme b to an apocytochrome ... more Background: Cytochrome c maturation (Ccm) is the covalent ligation of heme b to an apocytochrome c. Results: CcmE forms a stable ternary complex with CcmI and apocytochrome c. Conclusion: Together with CcmFHI, the heme chaperone CcmE is a part of the heme ligation complex that matures apocytochromes c. Significance: These findings contribute to our mechanistic understanding of how the Ccm process occurs in cells. Cytochrome c maturation (Ccm) is a post-translational process that occurs after translocation of apocytochromes c to the positive (p) side of energy-transducing membranes. Ccm is responsible for the formation of covalent bonds between the thiol groups of two cysteines residues at the heme-binding sites of the apocytochromes and the vinyl groups of heme b (protoporphyrin IX-Fe). Among the proteins (CcmABCDEFGHI and CcdA) required for this process, CcmABCD are involved in loading heme b to apoCcmE. The holoCcmE thus formed provides heme b to the apocytochromes. Catalysis of the thioether bonds between the apocytochromes c and heme b is mediated by the heme ligation core complex, which in Rhodobacter capsulatus contains at least the CcmF, CcmH, and CcmI components. In this work we show that the heme chaperone apoCcmE binds to the apocytochrome c and the apocytochrome c chaperone CcmI to yield stable binary and ternary complexes in the absence of heme in vitro. We found that during these protein-protein interactions, apoCcmE favors the presence of a disulfide bond at the apocytochrome c heme-binding site. We also establish using detergent-dispersed membranes that apoCcmE interacts directly with CcmI and CcmH of the heme ligation core complex CcmFHI. Implications of these findings are discussed with respect to heme transfer from CcmE to the apocytochromes c during heme ligation assisted by the core complex CcmFHI.

Biomolecules, Mar 31, 2021

Research Square (Research Square), Jul 28, 2020

Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a preval... more Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10000 people globally. The cell surface proteins or surfaceome serve as an information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation of surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in cell-based system identi ed that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have 'direct' access to drugs, they are appealing targets for cancer therapy. However, a comprehensive aberrant GBM surfaceome landscape has not been fully de ned. Thus, this study aimed to de ne GBM-speci c surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods: We integrated the RNA-Seq data from TCGA GBM (n=166) and GTEx normal brain cortex (n=408) databases to identify the signi cantly dysregulated surfaceome in GBM. This was followed by integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-con dence GBM surfaceome signature. Results: Of the 2,381 signi cantly dysregulated genes in GBM, 395 genes were classi ed as surfaceome. Via the integrative analysis, we identi ed 6 high-con dence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were signi cantly upregulated in GBM. The expression of these genes were validated in an independent transcriptomics database, which con rmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is signi cantly associated with poor disease-free survival. Last, using the Drugbank database, we identi ed several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions: In summary, we identi ed and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to e cient diagnostic/prognostic markers or potential treatment options for GBM.

Frontiers in Pediatrics, Mar 11, 2021

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and ... more Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.

Biosensors, Jun 7, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Cancers

Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic a... more Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease’s metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facili...

International Journal of Molecular Sciences

Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-alle... more Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGF...

Frontiers in Pediatrics

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and ... more Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down ...

Cells

Breast cancer is the leading cause of cancer-related deaths in women. The aggressive breast cance... more Breast cancer is the leading cause of cancer-related deaths in women. The aggressive breast cancer subtype is commonly linked to the genetic alterations in the TP53 tumor suppressor gene, predominantly the missense mutations. Robust experimental models are needed to gain better insights into these mutations’ molecular properties and implications in tumorigenesis. The generation of such models harboring the alterations is feasible with the CRISPR-based gene editing technology. Moreover, the development of new CRISPR applications, particularly DNA base and prime editing, has considerably improved the precision and versatility of gene editing. Here, we employed the prime editing tool to revert a TP53 missense C > T mutation (L194F) in a T47D luminal A breast cancer cell line. In parallel, this prime editing tool was also utilized to introduce the L194F mutation in HEK293T cells. To assess the prime editing efficiency in both cell lines, we first performed Sanger sequencing in the pr...

Journal of Biomedical Science, 2022

A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encod... more A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encoded protein (SEP) which comprises ≤ 100 amino acids. Traditionally dismissed by genome annotation pipelines as meaningless noise, sORFs were found to possess coding potential with ribosome profiling (RIBO-Seq), which unveiled sORF-based transcripts at various genome locations. Nonetheless, the existence of corresponding microproteins that are stable and functional was little substantiated by experimental evidence initially. With recent advancements in multi-omics, the identification, validation, and functional characterisation of sORFs and microproteins have become feasible. In this review, we discuss the history and development of an emerging research field of sORFs and microproteins. In particular, we focus on an array of bioinformatics and OMICS approaches used for predicting, sequencing, validating, and characterizing these recently discovered entities. These strategies include RIBO-S...

Additional file 2 Supplementary Fig. S1. Gene ontology and deregulated pathways in GBM. (A-B) Gen... more Additional file 2 Supplementary Fig. S1. Gene ontology and deregulated pathways in GBM. (A-B) Gene ontology cellular component of the significantly (A) upregulated and (B) downregulated genes in GBM. (C-D) KEGG pathway analysis of the (C) upregulated and (D) downregulated genes in GBM. Supplementary Fig. S2. Significant differentially expressed cell-surface genes in GBM. (A) GBM surfaceome classification using previously annotated cell surface genes dataset identifies 395 DEGs that belongs to surfaceome. (B) Cell surface genes stratification from (A) based on its subclass. Supplementary Fig. S3. KEGG pathway analysis of differentially expressed surfaceome in GBM. (A) Upregulated surfaceome and (B) Downregulated surfaceome. Supplementary Fig. S4. Mapping the expression of 87-gene modules from (Fig. 4A) with scRNA-seq data from [26] on the basis of GBM cell microenvironment. Supplementary Fig. S5. Significant upregulation of the prioritized GBM surfaceome signature in GBM patients. (A...